title: Epoxyeicosatrienoic acids prevent cisplatin-induced renal apoptosis through a p38 mitogen-activated protein kinase-regulated mitochondrial pathway.
abstract: Soluble epoxide hydrolase (sEH) catalyzes the conversion of epoxyeicosatrienoic acids into less active eicosanoids, and inhibitors of sEH have anti-inflammatory and antiapoptotic properties. Based on previous observations that sEH inhibition attenuates cisplatin-induced nephrotoxicity by modulating nuclear factor-κB signaling, we hypothesized that this strategy would also attenuate cisplatin-induced renal apoptosis. Inhibition of sEH with AR9273 [1-adamantan-1-yl-3-(1-methylsulfonyl-piperidin-4-yl-urea)] reduced cisplatin-induced apoptosis through mechanisms involving mitochondrial apoptotic pathways and by reducing reactive oxygen species. Renal mitochondrial Bax induction following cisplatin treatment was significantly decreased by treatment of mice with AR9273 and these antiapoptotic effects involved p38 mitogen-activated protein kinase signaling. Similar mechanisms contributed to reduced apoptosis in Ephx2(-/-) mice treated with cisplatin. Moreover, in pig kidney proximal tubule cells, cisplatin-induced mitochondrial trafficking of Bax and cytochrome c, caspase-3 activation, and oxidative stress are significantly attenuated in the presence of epoxyeicosatrienoic acids (EETs). Collectively, these in vivo and in vitro studies demonstrate a role for EETs in limiting cisplatin-induced renal apoptosis. Inhibition of sEH represents a novel therapeutic strategy for protection against cisplatin-induced renal damage.
authors.affiliation: Departments of Bioengineering and Therapeutic Sciences (Y.L., X.L., S.N., D.L.K.) and Anatomic Pathology (J.L.O.), University of California San Francisco, San Francisco, California; and Arête Therapeutics, Hayward, California (H.K.W.).
authors.forename: Yingmei
authors.initials: Y
authors.lastname: Liu
authors.forename: Xiaodan
authors.initials: X
authors.lastname: Lu
authors.forename: Sinh
authors.initials: S
authors.lastname: Nguyen
authors.forename: Jean L
authors.initials: JL
authors.lastname: Olson
authors.forename: Heather K
authors.initials: HK
authors.lastname: Webb
authors.forename: Deanna L
authors.initials: DL
authors.lastname: Kroetz
mesh_terms: D015126:8,11,14-Eicosatrienoic Acid / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000378:metabolism; D002460:Cell Line; D002945:Cisplatin / Q000633:toxicity*; D004789:Enzyme Activation; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors / Q000378:metabolism; D004852:Epoxy Compounds / Q000378:metabolism* / Q000494:pharmacology; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D013482:Superoxide Dismutase / Q000378:metabolism; D013552:Swine; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D004852:Epoxy Compounds; D017382:Reactive Oxygen Species; C046783:11,12-epoxy-5,8,14-eicosatrienoic acid; D013482:Superoxide Dismutase; D048051:p38 Mitogen-Activated Protein Kinases; D004851:Epoxide Hydrolases; D053148:Caspase 3; D015126:8,11,14-Eicosatrienoic Acid; D002945:Cisplatin